Anaesth Crit Care Pain Med 37 (2018) 481–491

Guidelines

Targeted temperature management in the ICU: Guidelines from a

French expert panel§
Alain Cariou a,*, Jean-Francois Payen b, Karim Asehnoune n, Gérard Audibert i, Astrid Botte o,
Olivier Brissaud p, Guillaume Debaty m, Sandrine Deltour s, Nicolas Deye f,
Nicolas Engrand j, Gilles Francony a, Stéphane Legriel g, Bruno Levy h, Philippe Meyer q,
Jean-Christophe Orban k, Sylvain Renolleau r, Bernard Vigué l, Laure de Saint Blanquat d,
Cyrille Mathien c, Lionel Velly e, Société de réanimation de langue française (SRLF)the
Société française d’anesthésie et de réanimation (SFAR)in conjunction with the
Association de neuro-anesthésie réanimation de langue française (ANARLF)the Groupe
francophone de réanimation et urgences pédiatriques (GFRUP)the Société française de
médecine d’urgence (SFMU)the Société française neuro-vasculaire (SFNV)
a
Medical Intensive Care Unit, Cochin University Hospital (AP–HP), Paris Descartes University, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France
b
Pôle anesthesie-réanimation, hôpital Michallon, CHU Grenoble Alpes, 38000 Grenoble, France
c
Service de réanimation médicale, centre hospitalier Mulhouse, Mulhouse, France
d
Hôpital Necker–Enfants-Malades, réanimation pédiatrique polyvalente, Assistance publique–Hôpitaux de Paris, Paris, France
e
Service d’anesthésie-réanimation, hôpital de la Timone, Assistance publique–Hôpitaux de Marseille, Marseille, France
f
Hôpital Lariboisiere, Assistance publique–Hôpitaux de Paris, Paris, France
g
Centre hospitalier de Versailles, Le Chesnay, France
h
Hôpital Central, CHU de Nancy, Nancy, France
i
CHU de Nancy, Nancy, France
j
Fondation Rothschild, Paris, France
k
Hôpital Pasteur 2, CHU de Nice, Nice, France
l
Anesthésie-réanimation, Bicêtre, France
m
CHU de Grenoble, La Tronche, France
n
Hôpitial Hôtel-Dieu, CHU de Nantes, Nantes, France
o
Hôpital Jeanne-de-Flandre, CHRU de Lille, Lille, France
p
CHU de Bordeaux, Bordeaux, France
q
Hôpital Necker–Enfants-Malades, Assistance publique–Hôpitaux de Paris, Paris, France
r
Hôpital Armand-Trousseau, Assistance publique–Hôpitaux de Paris, Paris, France
s
Hôpital Pitié-Salpêtrière, Assistance publique–Hôpitaux de Paris, Paris, France

A R T I C L E I N F O A B S T R A C T

Article history: Over the recent period, the use of induced hypothermia has gained an increasing interest for critically ill
Available online 5 July 2017 patients, in particular in brain-injured patients. The term ‘‘targeted temperature management’’ (TTM)
has now emerged as the most appropriate when referring to interventions used to reach and maintain a
Keywords: specific level temperature for each individual. TTM may be used to prevent fever, to maintain
Intensive care unit normothermia, or to lower core temperature. This treatment is widely used in intensive care units,
Guidelines mostly as a primary neuroprotective method. Indications are, however, associated with variable levels of
Targeted temperature management
evidence based on inhomogeneous or even contradictory literature. Our aim was to conduct a systematic
analysis of the published data in order to provide guidelines. We present herein recommendations for
the use of TTM in adult and paediatric critically ill patients developed using the Grading of
Recommendations Assessment, Development, and Evaluation (GRADE) method. These guidelines were
conducted by a group of experts from the French Intensive Care Society (Société de réanimation de langue
française [SRLF]) and the French Society of Anesthesia and Intensive Care Medicine (Société francaise

§
This article is being published jointly in Anaesthesia Critical Care & Pain Medicine and Annals of Intensive Care. The manuscript validated by the board meeting of SFAR and
SRLF (18/02/2016).
* Corresponding author.
E-mail address: alain.cariou@aphp.fr (A. Cariou).

http://dx.doi.org/10.1016/j.accpm.2017.06.003
2352-5568/! C 2017 The Author(s). Published by Elsevier Masson SAS on behalf of Société française d’anesthésie et de réanimation (Sfar). This is an open access article under

the CC BY license (http://creativecommons.org/licenses/by/4.0/).

482 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491

d’anesthésie réanimation [SFAR]) with the participation of the French Emergency Medicine Association
(Société française de médecine d’urgence [SFMU]), the French Group for Pediatric Intensive Care and
Emergencies (Groupe francophone de réanimation et urgences pédiatriques [GFRUP]), the French National
Association of Neuro-Anesthesiology and Critical Care (Association nationale de neuro-anesthésie
réanimation française [ANARLF]), and the French Neurovascular Society (Société française neurovasculaire
[SFNV]). Fifteen experts and two coordinators agreed to consider questions concerning TTM and its
practical implementation in five clinical situations: cardiac arrest, traumatic brain injury, stroke, other
brain injuries, and shock. This resulted in 30 recommendations: 3 recommendations were strong
(Grade 1), 13 were weak (Grade 2), and 14 were experts’ opinions. After two rounds of rating and
various amendments, a strong agreement from voting participants was obtained for all 30 (100%)
recommendations, which are exposed in the present article.
!C 2017 The Author(s). Published by Elsevier Masson SAS on behalf of Société française d’anesthésie et de

réanimation (Sfar). This is an open access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/).

with variable levels of evidence based on inhomogeneous or even

Guidelines committee (SFAR)
D. Fletcher, L. Velly, J. Amour, S. Ausset, G. Chanques,
V. Compère, F. Espitalier, M. Garnier, E. Gayat, J.Y. Lefrant,
J.M. Malinovsky, B. Rozec, B. Tavernier.
Guidelines and evaluation committee (SRLF)
L. Donetti, M. Alves, T. Boulain, O. Brissaud, V. Das, L. de Saint
Blanquat, M. Guillot, K. Kuteifan, C. Mathien, V. Peigne,
F. Plouvier, D. Schnell, L. Vong.
1. Introduction
The protective effects of hypothermia were first studied and
described in the late 1950s and then seem to have been forgotten
for roughly 20 years before intensivists revived interest in this
therapeutic method [1,2]. Experimental data show that the
neuroprotective effects of therapeutic hypothermia occur through
several mechanisms of action:
" reducing brain metabolism, which restores a favourable balance
with cerebral blood flow in injured brain tissue [3,4];
" lowering the intracranial pressure;
" reducing the initiation of brain cell apoptosis, notably the
caspase activation pathway, and of necrosis [5];
" decreasing the local release of lactate and of excitotoxic
compounds, such as glutamate, that is associated with alteration
in calcium homoeostasis during brain ischaemia [6–8];
" reducing brain tissue inflammatory response and systemic
inflammatory response syndrome [7,9];
" decreasing the production of free radicals [7,10];
" limiting the vascular and cell membrane permeability as seen in
brain ischaemia [10].
Accordingly, the use of mild to moderate hypothermia has
gained interest for critically ill patients, in particular brain-injured
patients in order to limit the extension of initial brain lesions
[11]. This can be achieved through various methods and targeted
temperatures. The term ‘‘targeted temperature management’’
(TTM) has emerged as the most appropriate referring to inter-
ventions used to reach and maintain a specific level temperature
for each individual.
The level of targeted temperature may differ according to the
situation. TTM may be used to prevent fever, to maintain
normothermia, or to lower core temperature. TTM is widely used
in intensive care units (ICUs) as a primary neuroprotective method,
i.e. in order to protect against neuronal injury or degeneration in
the central nervous system. Its indications are, however, associated
contradictory literature. Our aim was to conduct a systematic
analysis of the literature in order to edit national guidelines.
2. Methods
These guidelines were conducted by a group of experts for the
French Intensive Care Society (Société de réanimation de langue
française [SRLF]) and the French Society of Anesthesia and Intensive
Care Medicine (Société francaise d’anesthésie réanimation [SFAR]).
The organization committee defined a list of questions to be
addressed and designated experts in charge of each question. The
questions were formulated using the PICO (Patient Intervention
Comparison Outcome) format (http://www.gradeworkinggroup.
org/).
The method used to elaborate these recommendations was the
GRADE1 method [12]. Following a quantitative literature analysis,
this method is used to separately determine the quality of available
evidence, i.e. estimation of the confidence needed to analyse the
effect of the quantitative intervention, and the level of recommen-
dation. The quality of evidence is rated as follows:
" high-quality evidence: further research is very unlikely to
change the confidence in the estimate of the effect;
" moderate-quality evidence: further research is likely to have an
impact on the confidence in the estimate of the effect and may
change the estimate of the effect itself;
" low-quality evidence: further research is very likely to have an
impact on the confidence in the estimate of the effect and is
likely to change the estimate of the effect itself;
" very low-quality evidence: any estimate of the effect is very
unlikely.
The level of recommendation is binary (either positive or
negative) and strong or weak:
" strong recommendation: we recommend (GRADE 1+) or we do
not recommend to do (GRADE 1#);
" weak recommendation: we suggest (GRADE 2+) or we do not
suggest to do (GRADE 2#).
The strength of the recommendations is determined according
to key factors and validated by the experts after a vote, using the
Delphi and GRADE Grid method [13] that encompasses the
following criteria:
" the estimate of the effect;
" the global level of evidence: the higher the level of evidence, the
stronger the recommendation;
" the balance between desirable and undesirable effects: the more
favourable the balance, the stronger the recommendation;
 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491
" values and preferences: in case of uncertainty or large variability,
the level of evidence of the recommendation is probably weak,
and values and preferences must be more clearly obtained from
the affected persons (patient, physician, and decision-maker);
" cost: the greater the costs or the use of resources, the weaker the
recommendation.
The elaboration of a recommendation requires that at least 50%
of voting participants have an opinion and that less than 20% of
participants vote for the opposite proposition. The elaboration of a
strong agreement requires the agreement of at least 70% of voting
participants.
3. Results
3.1. Areas of recommendations
Fifteen experts and two coordinators agreed to consider
questions concerning TTM and its practical implementation in
five clinical situations in the intensive care setting: cardiac arrest
(CA), traumatic brain injury (TBI), stroke, other brain injuries, and
shock. The PubMed and Cochrane databases were searched for full
articles written in English or French published after January
2005 and June 2015. In case of an absence or a very low number of
publications during the considered period, the timing of publica-
tions could have been extended to 1995. The paediatric literature
had a specific analysis.
The experts summarized the work and applied the GRADE1
method, resulting in 30 recommendations: 3 recommendations
were strong (Grade 1), 13 were weak (Grade 2), and 14 were expert
opinions. After two rounds of rating and various amendments, a
strong agreement from voting participants was obtained for all 30
(100%) recommendations.
3.1.1. TTM after cardiac arrest
R1.1 We recommend using TTM in order to improve survival
with good neurological outcome in patients resuscitated from
out-of-hospital cardiac arrest (OHCA) with shockable cardiac
rhythm (ventricular fibrillation and pulseless ventricular tachy-
cardia) and who remain comatose after return of spontaneous
circulation (ROSC).
(Grade 1+)
Rationale: Seven meta-analyses [14–20] and 4 systematic
reviews [13,21–23] assessed studies on targeted TTM after CA, but
none identified separately patients with initial shockable versus
non-shockable rhythm. Two studies with patients presenting
initial shockable rhythm have been retained in the analysis [24,25]
and were in favour of the TTM use in this population. These trials
(one pseudo-randomized [24] and one randomized [25]) found
improved neurological outcome for OHCA patients with an initial
shockable rhythm. Several studies were not included in the present
analysis:
" the TTM trial [26] because of the absence of a group with no
control of body temperature, i.e. the trial compared TTM at 33 8C
versus TTM at 36 8C;
" a trial comparing a combination of hemofiltration with TTM
versus hemofiltration alone versus no hemofiltration and no
TTM [27];
" clinical trials that assessed pre-hospital TTM.
Observational studies, before–after studies, and matched
cohort studies found results in favour of TTM use, despite a low
483
to very low level of evidence [18]. International guidelines using
the GRADE method and including Bernard [24] and HACA [25]
trials strongly recommended the use of TTM for OHCA patients
with an initial shockable rhythm to increase survival with good
neurological outcome [13]. A recent meta-analysis also supports
the use of TTM in this population [14].
R1.2 We suggest considering TTM in order to improve survival
with good neurological outcome in patients resuscitated from
OHCA with non-shockable cardiac rhythm (asystole or pulse-
less electrical activity) and who remain comatose after ROSC.
(Grade 2+)
Rationale: Among 8 meta-analyses [14–20,28] and 4 reviews
[13,21–23] on TTM after CA, 1 meta-analysis specifically analysed
patients with initial non-shockable rhythm [28]. This meta-
analysis found decreased hospital mortality in patients with
TTM: RR 0.86 (95% CI 0.76–0.99), but there was no difference
regarding neurological outcome: RR 0.96 (95% CI 0.90–1.02). One
randomized control trial [29] with a limited sample size (n = 30)
compared patients treated with TTM versus no TTM and found no
difference between the 2 groups. Most observational studies (low
to very low level of evidence) did not observe significant between
groups differences. Although some studies were in favour of TTM
use in this population [30–32], a majority of studies did not report
a clinical improvement by using TTM [33–38]. Based on the poor
prognosis in this population and considering the lack of
therapeutic alternatives, the experts considered that TTM could
be suggested in this population.
R1.3 We suggest considering TTM in order to increase survival
with good neurological outcome in patients resuscitated from
in-hospital cardiac arrest (IHCA) who remain comatose after
ROSC.
(Expert opinion)
Rationale: There are no published randomized controlled trials
with patients presenting in-hospital cardiac arrest (IHCA) patients.
From 4 studies having included patients with IHCA or OHCA, it was
not possible to separately analyse IHCA patients [37,39–41]. In the
overall population, the results are either in favour of TTM [31,42] or
neutral [34,37,39–41].
R1.4 We suggest considering TTM between 32 and 36 8C in
order to improve survival with good neurological outcome
after CA.
(Grade 2+)
Rationale: Two studies with a high level of evidence and
consistent results addressed this question [14,26]. One random-
ized controlled trial included 939 patients and found no significant
difference in survival and neurological outcome between TTM at
33 8C versus TTM at 36 8C [26]. Similar results were reported in a
meta-analysis [14]. This meta-analysis included 6 randomized
studies using different degrees of temperature [24–27,29,43] and
concluded that a TTM strategy using a targeted
temperature < 34 8C might improve outcome compared to a
strategy with no TTM. A randomized controlled trial [43]
comparing TTM at 32 versus 34 8C was not included in our
analysis because this pilot trial included 36 patients only. A
retrospective study, not retained in the analysis, found a better
outcome at TTM 32–34 8C versus spontaneous normothermia
below 37.5 8C [44]. Post-hoc study derived from the TTM trial [26]
484 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491
was also not included to avoid duplicate data: it was found a
possible worsening in outcome in the TTM 33 8C group for patients
with shock at hospital admission [45]. Overall, targeted tempe-
ratures in clinical studies can be ranged between 32 and 36 8C,
although it is not possible to define the optimal temperature
within this range.
R1.5 We do not suggest initiating TTM with infusion of large
volumes of cold saline solution during transportation to the
hospital after CA.
(Grade 2#)
Rationale: Several randomized studies reported that pre-
hospital infusion of cold fluids was not associated with improved
outcome, whether this administration was conducted during
resuscitation (intra-arrest cooling) or after ROSC [46–50]. In
one randomized controlled trial [46], pre-hospital infusion of
large volumes of cold saline solution (4 8C) was associated with
increased occurrence of re-arrest after ROSC and of pulmonary
oedema [46]. Alternative methods of pre-hospital cooling were
too limited to assess impact on outcome [24,51]. The impact of
shortening time to reach TTM during the induction phase
of TTM is discussed elsewhere (R6.1). Conversely, any onset of
hyperthermia after ROSC appears deleterious in terms of out-
come [52,53].
R1.1 Paediatric – In comatose children following resuscitation
from OHCA or IHCA with a shockable or a non-shockable
cardiac rhythm, we recommend using TTM to maintain nor-
mothermia in order to improve neurological outcome.
(Expert opinion)
R1.2 Paediatric – In comatose children following resuscitation
from OHCA or IHCA with a shockable or a non-shockable
cardiac rhythm, we do not suggest using TTM between
32 and 34 8C to improve survival with good neurological
outcome.
(Grade 2#)
Rationale: In a randomized study [54], 270 children (2 days–
18 years) with OHCA were compared: 142 children allocated to
TTM at 33 8C versus 128 to TTM 36–37.5 8C during 5 days. There
was no significant difference between groups in survival rate with
good neurological outcome. In this population, hypoxia was the
main cause of OHCA (72%), which may explain why these results
differed from adults [24,25]. In a recent study, TTM lower than
32 8C was associated with higher mortality rate [55]. Other
retrospective or prospective studies had limited population size,
and mixed OHCA and IHCA, cardiac and respiratory causes.
Although hypothermia was still recommended in 2010 [56,57],
the latest recommendations by the International Liaison Commit-
tee on Resuscitation (ILCOR) endorsed the latest trials and did not
recommend any longer using hypothermia in children who remain
comatose after resuscitation CA [58].
3.1.2. TTM after traumatic brain injury
R2.1 In patients with severe traumatic brain injury, we suggest
considering TTM at 35–37 8C in order to control intracranial
pressure.
(Grade 2+)
Rationale: In a case–control series of patients with severe
traumatic brain injury (TBI), Puccio et al. [59] showed that patients
with TTM maintained at 36–36.5 8C within 72 h of TBI presented a
lower averaged intracranial pressure (ICP) and fewer episodes of
ICP > 25 mmHg as compared with patients who did not receive
TTM. Several series of clinical cases [60–62] showed a correlation
between core temperature, brain temperature, and ICP. However,
there is no randomized controlled study showing that TTM at 35–
37 8C in patients with severe TBI was associated with prevention of
intracranial hypertension.
R2.2 In patients with severe traumatic brain injury, we suggest
considering TTM at 35–37 8C to improve survival with good
neurological outcome.
(Grade 2+)
Rationale: In patients with TBI, hyperthermia is associated with
higher mortality rates [63,64], unfavourable neurological outcome
[63–66], and prolonged length of stay in the ICU and in the hospital
[63,67,68]. A cohort of patients with head injury (65% of TBI) did
not show improved neurological outcome in patients who received
TTM as compared with historical controls with no TTM [69]. There
is yet no randomized controlled study showing that TTM in
patients with TBI is associated with improved neurological
outcome, reduced mortality rate, or length of hospital stay.
Despite the low level of evidence, the aggravated outcome
associated with hyperthermia supports the recommendation to
maintain TTM between 35 and 37 8C.
Several studies with a higher level of evidence [70–74] and
meta-analyses [75–77] in adults and children showed no benefit
regarding mortality or neurological outcome with the use of
therapeutic hypothermia between 32 and 35 8C, compared to
normothermia in patients with severe TBI whether they had
intracranial hypertension or not.
R2.3 In TBI patients with refractory intracranial hypertension
despite medical treatments, we suggest considering TTM at
34–35 8C in order to lower ICP.
(Grade 2+)
Rationale: Several studies showed that TTM at 34–35 8C could
lower ICP [70,75,78–84], while this effect was not confirmed
elsewhere [71,72], and a raised in ICP was seen during rewarming
[69]. Polderman et al. [85] showed in 136 patients (64 patients
receiving barbiturates + hypothermia versus 72 patients receiving
barbiturates alone) that therapeutic hypothermia was superior to
barbiturates alone to treat high ICP and was associated with a
reduced mortality rate. In the Eurotherm trial [86], which is the
first randomized, multicentre study in a population of TBI patients
with ICP above 20 mmHg, 195 patients were treated with TTM
(32–35 8C) versus 192 patients treated with normothermia. High
ICP was easier to control in patients of the TTM group (barbiturates
were used in 41 control patients versus 20 TTM patients). However,
several studies found no additional clinical benefit where lowering
temperature below 34 8C. In 22 patients with severe head injury,
Shiozaki et al. [87] found that intracranial hypertension persisting
at 34 8C was not reduced any further by lowering the temperature
up to 31 8C. Using multimodal monitoring, hypothermia below
35 8C showed no benefit regarding brain tissue oxygen tension
(PtiO2) or biomarkers of brain metabolism [60], and this strategy
has a deleterious effect on these parameters [88]. TTM between
32 and 35 8C to treat high ICP can result in side effects, e.g.
respiratory infections, which are proportional to the duration and/
or depth of hypothermia [75,76].
 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491
The duration of hypothermia should be adapted according
to the persistence of intracranial hypertension. In a study of
215 patients with severe TBI, a 5-day duration of hypother-
mia resulted in better control of ICP and neurological outcome
than a 2-day period. In addition, rewarming after 5 days resulted
in less rebound effect of ICH than after 2 days [89]. The
meta-analysis of McIntyre et al. [90] was in line with these
findings.
Sustained elevation of ICP is an independent factor of
poor outcome after TBI. Uncontrolled studies indicated that
therapeutic hypothermia to treat high ICP could be associated
with better outcome [77,78,82,91]. However, the Eurotherm study
[86] showed that TTM had a negative effect on neurological
outcome at 6 months with an odds ratio of unfavourable outcome
after adjustment at 1.53 (1.02–2.30) (P = 0.04); favourable
outcome (Glasgow Outcome Scale Extended score 5–8) 26% in
the TTM 32–35 group versus 37% for patients in the control
group (P = 0.03). It should be noted that ICP was moderately
elevated in that trial, i.e. 20–30 mmHg and of short-term duration
(5 min), and that therapeutic hypothermia was initiated with cold
saline infusion prior to using treatments for high ICP (osmotic
therapy).
R2.1 Paediatric – In children with severe traumatic brain injury,
we recommend using TTM at normothermia.
(Expert opinion)
R2.2 Paediatric – In children with severe traumatic brain injury,
we do not recommend using TTM at 32–34 8C to improve
outcome or control intracranial hypertension.
(Grade 1#)
Rationale: A randomized study including 225 patients [70] and
another one with 77 patients, which was terminated prematurely
because of futility [73], support the conclusion that moderate
hypothermia (32–34 8C) provides no benefit in terms of outcome in
severely brain-injured children. A post-hoc study by Hutchison
et al. [92] showed a higher incidence of low arterial blood pressure
and low cerebral perfusion pressure during moderate hypothermia
(32–34 8C). A retrospective study in 117 severe TBI children
identified early hyperthermia as an independent factor associated
with aggravated outcome (OR for lower Glasgow Coma Scale score
at PICU discharge: 4.7, CI 1.4–15.6; OR for longer length of stay in
PICU: 8.5, CI 2.8–25.6) [93]. TTM may reduce ICP in TBI children as
seen in adults.
3.1.3. TTM after stroke, intracerebral haemorrhage, and subarachnoid
haemorrhage
R3.1 We suggest considering TTM at normothermia during the
early phase of severe ischaemic stroke.
(Expert opinion)
Rationale: Hyperthermia or fever is a frequent complication
(> 50%) in patients at the acute phase of stroke and is correlated
with poor functional outcome [63]. However, the efficacy of
therapeutic hypothermia has not yet been shown, according to
6 randomized trials that tested hypothermia (33–35 8C) in stroke
patients [94–99]. There were few patients and methodological
biases were numerous. A single study [99] investigated patients
with severe stroke (NIHSS > 15). Two randomized studies are
ongoing: EuroHYP-1 [100] explores the value of 24 h; 34–35 8C
485
hypothermia following recent stroke, and the recent ICTuS 2/3 trial
[101]. In that later study, intravascular therapeutic hypothermia
was found safe and feasible in patients treated with recombinant
tissue-type plasminogen activator.
Routine use of antipyretics is commonly recommended in
patients with hyperthermia, though there is no evidence of
their impact on neurological outcome or mortality. The meta-
analysis of Ntaios et al. [102] that included 4 major random-
ized trials [103–106] found no difference in mortality or
neurological outcome between hypothermia and hyperthermia
(> 38 8C).
R3.2 – In comatose patients with spontaneous intracerebral
haemorrhage, we suggest considering TTM at 35–37 8C to
lower intracranial pressure.
(Expert opinion)
Rationale: Observational studies showed that fever is indicative
of poor neurological outcome after intracerebral haemorrhage
[107,108]. However, most of these studies were observational,
with a small number of patients and methodological biases. Two
observational studies showed that hypothermia at 35 8C over 8–10
days had a favourable effect on peri-haemorrhagic oedema and ICP,
with no benefit on neurological outcome [109,110]. A case–control
study using TTM at 37 8C found no effect on neurological outcome
at ICU discharge, while the duration of mechanical ventilation and
length of stay in the ICU was prolonged in patients treated with
TTM [111]. The effect of hypothermia at 35 8C during 8 days is
ongoing in patients with a large intracerebral haemorrhage (25–
64 mL) (CINCH trial) [112].
R3.3 – In comatose patients with aneurysmal subarachnoid
haemorrhage, we suggest considering TTM to lower ICP and/or
to improve neurological outcome.
(Expert opinion)
Rationale: Observational studies showed that fever is predictive
of poor neurological outcome after subarachnoid haemorrhage
[113–115]. Most of these studies were observational, with a
small number of patients and methodological biases [116–
120]. These studies found a decrease in ICP and suggested that
the 12-month neurological outcome might be improved with the
use of normothermia and hypothermia (32–34 8C) in refractory
intracranial hypertension. A randomized controlled study [118]
compared normothermia (TTM at 36.5 8C) versus conventional
treatment for hyperthermia > 37.9 8C: no conclusion could
be drawn for the subgroup of patients with subarachnoid
haemorrhage.
R.3.1 Paediatric 3.1 Paediatric – In children with subarachnoid
haemorrhage, we suggest considering TTM between 36 and
37.5 8C to control intracranial pressure.
(Experts’ recommendation)
Rationale: There is no randomized controlled study that
explored the use of TTM and therapeutic hypothermia in
children with stroke, intracerebral haemorrhage, and/or subar-
achnoid haemorrhage. Reduction of intracranial pressure
was reported in one clinical case [121] and in a retrospective
study where fever control and therapeutic hypothermia were
used [122]. TTM may reduce ICP in children with SAH as seen
in adults.
486 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491
3.1.4. TTM in acute bacterial meningitis and status epilepticus
R4.1 In patients with refractory or super-refractory status
epilepticus, we suggest considering TTM at 32–35 8C to control
seizure activity.
(Expert opinion)
Rationale: Experimental studies [123–131] showed the anti-
convulsant properties of hypothermia that were confirmed in
patients with refractory or super-refractory status epilepticus
(lasting for more than 24 h) persisting despite maximum
treatment. A randomized controlled trial and several reports
showed that TTM (32–35 8C) for 24 h was associated with a better
control of electrical seizure activity and achievement of burst-
suppression pattern [132–134]. In the HYBERNATUS trial, the rate
of progression to EEG-confirmed status epilepticus was lower in
the hypothermia group than in the control group (11 vs. 22%; odds
ratio, 0.40; 95% CI 0.20–0.79; P = 0.009) [135].
R4.2 In comatose patients with meningitis or meningoenceph-
alitis, we do not suggest considering TTM when fever is
tolerated.
(Expert opinion)
Rationale: No interventional study tested the effect of TTM on
outcome of ICU patients with meningitis or meningoencephalitis.
Saxena et al. [136] showed that peak temperature in the first 24 h
of ICU admission did not increase the hospital mortality rate in
patients with infection of the central nervous system (CNS),
whereas it was associated with increased mortality rate in patients
with stroke and TBI. Other studies did not report consistent results
[137,138]. Interestingly, in the absence of infection, the outcome
was better if the temperature over the first 24 h peaked between
37.5 and 37.9 8C, whereas in case of infection, the outcome was
better if temperature peaked at 38–38.4 8C (UK database) or at 39–
39.4 8C (NZ/Australian database) [136]. Fever plays a protective
role because it inhibits replication of N. meningitidis and
S. pneumoniae [136] and eases the diagnosis of infection
[137]. The use of paracetamol in septic patients can decrease
temperature by 0.3 8C, but did not affect mortality or length of ICU
stay [139].
R4.3 In comatose patients with bacterial meningitis and no
intracranial hypertension, we suggest considering normother-
mia to improve survival and neurological outcome.
(Expert opinion)
Rationale: In ICU patients with bacterial meningitis, Mourvillier
et al. [140] found more deleterious effects in the induced
hypothermia group. No other study has been conducted on this
topic.
R4.4 – In comatose patients with bacterial meningitis and
intracranial hypertension, we suggest considering TTM at
34–36 8C to improve survival and neurological outcome.
(Expert opinion)
Rationale: In comatose patients with bacterial meningitis
and intracranial hypertension, hypothermia had a favourable
effect on non-invasive measurements of ICP [141]. However, the
control group was historical and 10 patients from a preliminary
study were probably included [142]. In a case report [143], TTM at
35–36 8C controlled refractory intracranial hypertension, in
combination with thiopental. In two other studies in patients
with severe viral encephalitis and intracranial hypertension,
outcome was better in cooled patients [144,145]. Similar findings
were obtained in other case reports [146–151].
R4.1 Paediatric – In children with status epilepticus, we suggest
considering TTM (normothermia) to improve outcome.
(Expert opinion)
Rationale: Few clinical cases of refractory or super-refractory
status epilepticus [152–154] and encephalitis in children
[152,155] treated with therapeutic hypothermia have been
reported. There is a lack of evidence to formalize recommendation.
A retrospective study in 43 heterogeneous patients (encephalitis
and encephalopathy – viruses, major hyperthermia, shock, status
epilepticus) [156] compared 16 patients under normothermia
versus 27 patients under therapeutic hypothermia. The cerebral
performance category score at 12 months was better in patients
under hypothermia. Maintaining normothermia in children with
status epilepticus may be appropriate.
3.1.5. TTM after haemodynamic shock
R5.1 We do not suggest considering TTM below 36 8C in
patients with cardiogenic shock.
(Grade 2#)
Rationale: There were 4 studies that investigated the effects of
moderate hypothermia [157–160]. They were retrospective or
uncontrolled, and the number of patients included was low.
Therapeutic hypothermia is feasible and not associated with an
increased incidence of adverse effects. A prospective study is in
progress (clinical trial.gov – NCT01890317).
R5.2 We do not suggest considering TTM below 36 8C in
patients with septic shock.
(Grade 2#)
R5.3 We suggest considering TTM at normothermia in patients
with septic shock.
(Grade 2)
Rationale: Among five randomized trials [161–164], three were
designed to evaluate non-steroidal anti-inflammatory drugs
versus placebo with a large proportion of patients without fever
in the 2 groups [161,162,164]. One study compared acetamino-
phen versus placebo in patients with fever [139]. These studies
showed that antipyretics effectively control temperature with no
reported side effects. There was no difference in mortality rate,
hemodynamic status, or length of stay in ICU. In one trial that
compared TTM versus no TTM, Schortgen et al. [163] found that the
vasopressor support (main endpoint) was significantly reduced in
the TTM group, as was the duration of shock. However, despite a
decreased mortality rate (secondary endpoint) at day 14 observed
in the TTM group, there was no difference in mortality rate at both
ICU and hospital discharge. TTM improved hemodynamic status in
one methodologically well-conducted study [163] in which
mortality was a secondary objective. All clinical studies concluded
that TTM is feasible in septic shock and is not associated with more
frequent side effects.
 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491
3.1.6. Implementation and monitoring of TTM
R6.1 We recommend using advanced methods with servo-
regulated cooling of central body temperature to optimize
TTM.
(Grade 1+)
Rationale: The present recommendation is based on post-
cardiac arrest patients. A greater efficacy of advanced methods
(‘‘servo-controlled’’) was constantly found, particularly during the
maintenance phase. The benefit of advanced methods during the
induction phase of TTM was however variable because it relied
upon the initial temperature. The incidence of overcooling/
overshooting was variable between advanced and basic methods.
Our analysis included 3 randomized studies [165–167] and
uncontrolled studies [168–171]. Regarding the neurological
outcome, results were discordant: one study found a trend in
favour of advanced methods [165], two studies were either
negative [166] or positive (though cerebral performance category
score was not reported) [167], and 4 studies gave variable results
[168–171]. Overall, these advanced methods might help to
optimize TTM, but their effect on survival with good neurological
outcome was not established [40].
R6.2 We suggest considering the control of rewarming in
patients treated with TTM.
(Expert opinion)
Rationale: After cardiac arrest, it is impossible to distinguish
effects associated with the rewarming period from those attributable
to induction and maintenance phase. Experts retained 2 randomized
trials [165,166] that found no differences between controlled and
passive rewarming. The rate of rewarming and the time to achieve
normothermia were found difference between controlled and
uncontrolled rewarming in non-randomized studies [178–180]. Re-
bound or post-rewarming fever was not always suppressed using
controlled rewarming [165,170–172]. Clinical studies found no
association between rewarming rate and outcome after adjustment
[165,171–174]. In brain trauma and stroke, a lower rate of
rewarming is important in order to prevent rebounds on ICP
[89,173,174]. However, no randomized trial has specifically ad-
dressed this issue other than indirect measurements of ICP [175].
R6.3 We suggest considering measurements of core body
temperature in patients treated with TTM.
(Grade 2+)
Rationale: Besides the brain as the most preferable site to measure
core body temperature, other sites can be used. Observational studies
assessed the agreement between the core body temperature and
other sites, i.e. oesophagus, bladder, rectum, nasopharynx, eardrum,
and skin [176–180]. Agreement between core body sites of
measurement (lungs, oesophagus, bladder, and rectum) was
correct. Correlation and agreement were poor for peripheral sites
of measurement (skin and tympanic) [176–180]. A study reported
a bias of 1 8C between core and tympanic temperature [178].
R6.4 We suggest considering the detection of several compli-
cations (sepsis, pneumonia, arrhythmia, hypokalaemia) in
patients treated with TTM.
(Grade 2+)
487
Rationale: The meta-analysis of Xiao et al. [181] found a trend
between the use of TTM and the incidence of infectious
complications, i.e. sepsis and pneumonia. Not included in this
meta-analysis are observational studies performed in large
populations [33,182–184]: they all found an increased incidence
of infectious complications in TTM patients. Hypokalaemia is the
most common metabolic derangement reported in TTM studies
[26]. Two studies reported an increased occurrence of hypo-
kalaemia (serum potassium < 3.5 mmol/L) [37,185] that was
confirmed in the meta-analysis of Xiao et al. [181]. This meta-
analysis found higher risk of cardiac arrhythmia in patients treated
with TTM [181].
R6.1 Paediatric – We suggest considering methods with servo-
regulated cooling of central body temperature in children
treated with TTM.
(Expert opinion)
Rationale: One randomized open controlled study showed the
superiority of a servo-controlled system in maintaining hypother-
mia in newborns with perinatal asphyxia managed in the pre-
hospital settings with therapeutic hypothermia [186]. Forty-nine
infants were allocated to a servo-controlled system, and 51 were
cooled according to the unit’s usual protocol (passive hypother-
mia). Newborns cooled with the servo-controlled device were
more often close to the target temperature upon arrival at the
hospital (median 73% [IQR 17–88] vs. 0% [IQR 0–52] P < 0.001). The
target temperature was more often reached during transport in
the servo-control group (80 vs. 49%, P < 0.001) and in a shorter
time (44 $ 31 vs. 63 $ 37 min, P = 0.04). The number of newborns
who reached the target temperature in 1 h was significantly higher in
the servo-control group than in the control group (71 vs. 20%,
P < 0.001).
R6.2 Paediatric – We suggest considering measurements of
core body temperature measurement in children treated with
TTM.
(Grade 2+)
Rationale: Several studies compared the accuracy of different
sites for temperature measurement in children. In a prospective
study (n = 15), peripheral sites (axillary, tympanic, rectal, oeso-
phageal) were compared to central blood measurements [187]. The
best agreement with blood temperature was obtained with
oesophageal measurements. Several other studies and meta-
analysis confirmed a poor agreement between axillary or tympanic
measurements and central blood temperature [188–190].
Authors’ contributions
AC and JFP proposed the elaboration of this recommendation
and manuscript in agreement with the ‘‘Société de réanimation de
langue française’’ and ‘‘Société française d’anesthésie et de réanima-
tion’’. LSB, CM, and LV wrote the methodology section and gave the
final version with the final presentation. ND and GD contributed to
elaborate recommendations and write the rationale of question 1
(cardiac arrest). BV, GF, JFP contributed to elaborate recommen-
dations and to write the rationale of question 2 (traumatic brain
injury). SD and GA contributed to elaborate recommendations and
to write the rationale of question 3 (stroke and subarachnoid
haemorrhage). SL and NE contributed to elaborate recommenda-
tions and to write the rationale of question 4 (acute bacterial
meningitis and status epilepticus). BL and KA contributed to
elaborate recommendations and to write the rationale of question
488 A. Cariou et al. / Anaesth Crit Care Pain Med 37 (2018) 481–491
5 (shock). JCO and ND contributed to elaborate recommendations
and to write the rationale of question 6 (implementation and
monitoring). AB, LSB, PM, and SR contributed to elaborate
recommendations and to write the rationale paediatric recom-
mendations. FA and YW provide references. AC, LV, and JFP drafted
the manuscript. All authors read and approved the final manu-
script.
Funding
This work was financially supported by the Société de
réanimation de langue française (SRLF) and the Société française
d’anesthésie et de réanimation (SFAR).
Disclosure of interest
Alain Cariou declares speaker fees and transport accommoda-
tion from Bard.
Nicolas Deye declares speaker fees, transport accommodation,
and research grants from BARD and ZOLL.
Nicolas Deye was also the primary investigator of the ICEREA
trial (partially granted by ALSIUS) and coordinator of the Cool
Study (CSZ-Meditherm).
Karim Asehnoune, Gérard Audibert, Astrid Botte, Olivier
Brissaud, Guillaume Debaty, Sandrine Deltour, Nicolas Engrand,
Gilles Francony, Bruno Levy, Cyrille Mathien, Philippe Meyer, Jean-
Christophe Orban, Jean-François Payen, Sylvain Renolleau, Laure de
Saint Blanquat, Lionel Velly, Bernard Vigué declare that they have
no competing interest.
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